Location of Repository

Computational prediction of splicing regulatory elements shared by Tetrapoda organisms

By Alexander Churbanov, Igor Vořechovský and Chindo Hicks

Abstract

Background: auxiliary splicing sequences play an important role in ensuring accurate and efficient splicing by promoting or repressing recognition of authentic splice sites. These cis-acting motifs have been termed splicing enhancers and silencers and are located both in introns and exons. They co-evolved into an intricate splicing code together with additional functional constraints, such as tissue-specific and alternative splicing patterns. We used orthologous exons extracted from the University of California Santa Cruz multiple genome alignments of human and 22 Tetrapoda organisms to predict candidate enhancers and silencers that have reproducible and statistically significant bias towards annotated exonic boundaries.<br/>Results: a total of 2,546 Tetrapoda enhancers and silencers were clustered into 15 putative core motifs based on their Markov properties. Most of these elements have been identified previously, but 118 putative silencers and 260 enhancers (~15%) were novel. Examination of previously published experimental data for the presence of predicted elements showed that their mutations in 21/23 (91.3%) cases altered the splicing pattern as expected. Predicted intronic motifs flanking 3' and 5' splice sites had higher evolutionary conservation than other sequences within intronic flanks and the intronic enhancers were markedly differed between 3' and 5' intronic flanks.<br/>Conclusion: difference in intronic enhancers supporting 5' and 3' splice sites suggests an independent splicing commitment for neighboring exons. Increased evolutionary conservation for ISEs/ISSs within intronic flanks and effect of modulation of predicted elements on splicing suggest functional significance of found elements in splicing regulation. Most of the elements identified were shown to have direct implications in human splicing and therefore could be useful for building computational splicing models in biomedical researc

Topics: QH426
Year: 2009
OAI identifier: oai:eprints.soton.ac.uk:69805
Provided by: e-Prints Soton

Suggested articles

Preview

Citations

  1. (2004). Aligning multiple genomic sequences with the threaded blockset aligner. Genome Res
  2. (2006). Ast G: Comparative analysis identifies exonic splicing regulatory sequences--The complex definition of enhancers and silencers. Mol Cell doi
  3. (2003). Ast G: Intronic sequences flanking alternatively spliced exons are conserved between human and mouse. Genome Res doi
  4. (2003). Bindereif A: HnRNP L stimulates splicing of the eNOS gene by binding to variable-length CA repeats. Nat Struct Biol doi
  5. (2002). BLAT--the BLAST-like alignment tool. Genome Res doi
  6. (2005). Blencowe BJ: Alternative splicing of conserved exons is frequently species-specific in human and mouse. Trends Genet doi
  7. (2007). Blencowe BJ: Global analysis of alternative splicing differences between humans and chimpanzees. Genes Dev doi
  8. (2006). Burge CB: Inference of splicing regulatory activities by sequence neighborhood analysis. PLoS Genet doi
  9. (2008). Burge CB: Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA doi
  10. (2004). Burge CB: Systematic identification and analysis of exonic splicing silencers. Cell doi
  11. (2003). Burge CB: Widespread selection for local RNA secondary structure in coding regions of bacterial genes. Genome Res doi
  12. (2008). CB: Alternative isoform regulation in human tissue transcriptomes. Nature doi
  13. (2006). CB: General and specific functions of exonic splicing silencers in splicing control. Mol Cell doi
  14. (2005). CB: Identification and analysis of alternative splicing events conserved in human and mouse. doi
  15. (2002). CB: Predictive identification of exonic splicing enhancers in human genes. Science doi
  16. CB: RESCUE-ESE identifies candidate exonic splicing enhancers in vertebrate exons. doi
  17. (2004). CB: Variation in sequence and organization of splicing regulatory elements in vertebrate genes. doi
  18. (2004). Chasin LA: Computational definition of sequence motifs governing constitutive exon splicing. Genes Dev doi
  19. (2000). Chasin LA: Human genomic sequences that inhibit splicing. Mol Cell Biol doi
  20. (2005). Conboy JG: The splicing regulatory element, UGCAUG, is phylogenetically and spatially conserved in introns that flank tissue-specific alternative exons. Nucleic Acids Res doi
  21. (2007). Discovery and analysis of evolutionarily conserved intronic splicing regulatory elements. PLoS Genet doi
  22. (2007). Emergence of novel color vision in mice engineered to express a human cone photopigment. Science doi
  23. (1989). Expression of the chicken vimentin gene in transgenic mice: efficient assembly of the avian protein into the cytoskeleton. Proc Natl Acad Sci USA doi
  24. (2005). Guigo R: Comparison of splice sites in mammals and chicken. Genome Res doi
  25. (2004). Haussler D: Ultraconserved elements in the human genome. Science
  26. (1998). Krainer AR: Identification of functional exonic splicing enhancer motifs recognized by individual SR proteins. Genes Dev doi
  27. (2002). Krainer AR: Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet doi
  28. (2006). Method of predicting splice sites based on signal interactions. Biol Direct
  29. (1981). Optimal computer folding of large RNA sequences using thermodynamics and auxiliary information. Nucleic Acids Res doi
  30. (2004). Pattern of sequence variation across 213 environmental response genes. Genome Res
  31. (2008). Phylogeny-aware gap placement prevents errors in sequence alignment and evolutionary analysis. Science doi
  32. (1994). RNA binding specificity of hnRNP A1: significance of hnRNP A1 high-affinity binding sites in premRNA splicing.
  33. (2007). S: Pre-mRNA secondary structures influence exon recognition. PLoS Genet doi
  34. (2004). Single nucleotide polymorphism-based validation of exonic splicing enhancers. PLoS Biol doi
  35. (2005). Target RNA motif and target mRNAs of the Quaking STAR protein. Nat Struct Mol Biol doi
  36. Thanaraj TA: ASD: a bioinformatics resource on alternative splicing.
  37. (2008). The UCSC Genome Browser Database: doi
  38. (2006). Using RNA secondary structures to guide sequence motif finding towards singlestranded regions. Nucleic Acids Res doi
  39. (2007). Vorechovsky I: Global control of aberrant splicesite activation by auxiliary splicing sequences: evidence for a gradient in exon and intron definition. Nucleic Acids Res doi
  40. (2006). Vorechovsky I: Position-dependent repression and promotion of DQB1 intron 3 splicing by GGGG motifs. doi
  41. (2008). Zhang MQ: RNA landscape of evolution for optimal exon and intron discrimination. doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.